Purpose.The purpose of this open
competition Funding Opportunity Announcement (FOA) is to stimulate the translation of innovative therapies
suitable for children with brain tumors from the laboratory to early phase
clinical testing. To achieve this goal, the National Cancer Institute (NCI)
intends to continue a Pediatric Brain Tumor Consortium (PBTC) program. The NCI will support one multi-center clinical trials
group (a “Consortium”) that will be responsible for timely conduct
of the Phase 1, Phase 2, and pilot studies evaluating novel treatment
approaches relevant to the pediatric brain tumor population. The
National Institute of Neurological Disorders and Stroke (NINDS), is
co-sponsoring this initiative because of a shared interest with NCI in the
treatment of pediatric brain tumors. NINDS will be involved in coordinating
PBTC activities across other NIH-supported normal and disease-oriented brain
imaging Networks (including the NCI-supported adult brain tumor consortium) as
well as in aspects related to the neurocognitive, quality-of-life impact of
certain treatments on long-term survivors of pediatric brain tumors. Each application submitted in response to this FOA must include
plans for (i) the PBTC Operations and Statistics/Data Centers and (ii) up to
seven member institutions. The proposed PBTC must be able to (i) conduct
Phase 1, Phase 2, and pilot clinical trials of novel treatment approaches for
children with brain tumors, focusing whenever
appropriate on clinical trials that require the specialized abilities of
the PBTC collaborating experienced neurosurgeons, neuro-oncologists, radiation
oncologists and neuroimagers; and (ii) conduct and/or support laboratory
studies related to PBTC clinical trials that may provide information relevant
to the success or failure of therapy.

Funds Available and Anticipated Number of Awards.The NCI
and NINDS intend to commit up to $2.2 million in total costs in FY 2009 and up
to $11.8 million over the planned 5 year project period to support one award.

Eligible Project Directors/Principal Investigators (PDs/PIs). Individuals
with the skills, knowledge, and resources necessary to carry out the proposed
research are invited to work with their institution/organization to develop an
application for support. Individuals from underrepresented racial and ethnic
groups as well as individuals with disabilities are always encouraged to apply
for NIH support.

Number of PDs/PIs.More than one PD/PI (i.e., multiple
PDs/PIs), may be designated on the application.

Number
of Applications.Applicants may submit only one application.

Resubmissions. Resubmission
applications are not permitted in
response to this FOA.

This Funding Opportunity Announcement (FOA) is
designed to continue the NCI’s support for the development of more effective therapies for
children with brain tumors. To address these needs, the NCI solicits
applications for the Pediatric Brain Tumor Consortium
(PBTC). The PBTC is expected to ensure that
(i) laboratory discoveries relevant to children with brain cancers are rapidly
translated into the clinical setting and (ii) novel treatment approaches for
children with brain tumors are expeditiously evaluated. In addition, the
PBTC should include a dedicated Neuroimaging Center. This center should be utilized in PBTC clinical trials to gain insights into the
effects of investigational treatments on both tumor and normal brain tissues.

Continuation of the NCI Pediatric Brain Tumor
Consortium program under this FOA will be based on an open competition as an
opportunity to reshape the PBTC and better serve the overall goals of the
program. Both the current PBTC awardee and other qualifying institutions
are encouraged to form teams (with appropriate candidates for Member
Institutions) to submit PBTC applications.

Background

NCI is the primary source of research funding
for early phase evaluations of new drugs and new treatment approaches for
children with cancer, including those with brain tumors. This NCI support has
increased the access of pediatric oncology patients to a broad range of new
anticancer agents and has helped to identify curative treatments for
approximately 80% of affected children. Nonetheless, 20% of children with
cancer succumb to their disease and a large fraction of survivors experience
significant short- and long-term toxicities. High mortality remains a problem
among some groups of pediatric patients, especially those with brain tumors (such as diffuse
intrinsic brain stem gliomas). Moreover, a substantial proportion of children
with brain cancers who survive after receiving current treatments exhibit
functional impediments. The PBTC program was initially proposed 10 years ago. This FOA represents a continuation of the NCI’s commitment to clinical
research for children with brain tumors as well as a forward-looking
program for extending targeted therapeutics into this patient population.

The scientific opportunities for advancing treatment options
for childhood brain tumors have expanded considerably. The molecular
characteristics of childhood brain cancers are understood far better today than
when the PBTC program was initially established. These advances are
paralleled by an expansion in the number and variety of anticancer agents
targeted towards specific signaling pathways that control growth and
proliferation of cancer cells. The combination of both factors, increased
understanding of cancer biology and availability of novel therapeutic
strategies, create clinical research opportunities for the PBTC to exploit.

The overall goal for the PBTC is to
identify new effective treatments for subsets of patients with tumors that show
specific, defined molecular characteristics. In the coming 5-year funding
period, the thrust of the PBTC effort will be in the following two directions
(both have to be addressed by all PBTC applicants):

1. Conduct of
Phase 1, Phase 2, and pilot clinical trials for safe
and efficient evaluation of novel treatment approaches suitable for
children with brain tumors. This direction should exploit new developments in
various venues, including: (i) PBTC member institutions, (ii) the NIH, (iii)
other academic institutions, and/or (iv) the for-profit
pharmaceutical/biotechnology sector. The focus
should be primarily on clinical trials that require the specialized
abilities of the PBTC’s collaborating experienced neurosurgeons,
neuro-oncologists, radiation oncologists and/or neuroimagers.

2. Incorporation
of pharmacokinetic and pharmacodynamic endpoints (to include imaging and
translational laboratory evaluations as appropriate) into PBTC clinical trials
to aid the development of the new treatment approaches.

Organizational
Requirements for the Proposed PBTC are as follows.

PBTC Scientific and
Organizational Leadership. Since a single award will cover the entire PBTC, applicants
are encouraged to take advantage of the multiple Principal Investigator (PI)
option. It is
expected that one PI, designated as the “lead PI”, will be
responsible for the scientific direction of the PBTC. Another PI should be
designated as the director of the Statistics and Data Center (see below).
Either of these PIs may also oversee (as a director) the Operation Center (see below). Other PIs may be designated as appropriate, e.g. “site”
leaders at the individual Member Institutions and PI of the Neuroimaging Center. The lead PI and center directors may also serve as
“site” PIs.

Operations Center. The PBTC must have a
single Operations Center that will be responsible for (1) preparing clinical trial protocol documents, (2) arranging meetings for the PBTC;
(3) assuring PBTC compliance with the requirements of the Food and Drug
Administration (FDA) pertinent to new therapies and Office for Human Research
Protections (OHRP) regarding human subjects; and (4) monitoring performance of
the PBTC Member Institutions. The Operations Center will also monitor and
provide reports on the PBTC’s performance in meeting pre-determined
timelines for: (1) preparation of Letter of Intent (LOI)/concept and
development of clinical trial protocol; (2) study implementation; (3)
publication of the results of PBTC-conducted studies; and (4) evaluation of
Member Institution performance. The proposed PBTC must have prescribed
procedures for corrective actions in case of failure by investigators and/or
institutions to meet these timelines.

Statistics and Data Center. The
PBTC must have a single Statistics and Data Center that will collect clinical
trials data directly from participating institutions using a remote data entry
system. Systems
for the management of PBTC clinical and
imaging data are expected to be compatible with the cancer Biomedical
Informatics Grid (caBIG™, https://cabig.nci.nih.gov/)
within the 5-year funding period.

Neuroimaging Center. The proposed PBTC must
include a Neuroimaging Center for the central collection and review of imaging
studies. In case of PBTC studies with imaging endpoints, the Neuroimaging Center will develop the imaging research plan for the study (in collaboration
with other radiologists and other imaging experts within the PBTC). The Neuroimaging Center will then be responsible for the collecting, analyzing, and archiving
imaging data as required by the plan. Applicants are encouraged to plan for the
PBTC Neuroimaging Center to collaborate on problems of mutual interest with
the Imaging Center of the adult brain tumor consortium and with other NIH
imaging networks.

Member Institutions. The proposed PBTC should
include up to seven Member Institutions. Collectively, these institutions
should be able to complete three to four clinical trials per year and to enroll
approximately 100-150 patients (in total at all sites) per year.

Applicants are
also advised to maximize their research potential by judicious selection of the
participating Member Institutions. For example, the previous PBTC awardee
submitting a renewal application may propose a revised membership list with new
candidate Member Institutions that are not listed on the current award.
Reciprocally, new PBTC applications may include candidate institutions that are
Member Institutions on the current award.

The candidate
institutions comprising the PBTC applicant team are expected to have the
following attributes:

Experience
in developing and participating in early phase clinical trials for children
with brain tumors;

Capability
of reporting clinical data in a timely manner to the PBTC data management
infrastructure (including the Statistics/Data Center, see below);

Ability
to contribute to the scientific leadership (e.g., in the areas of
pharmacokinetics, pharmacogenetics, and pharmacodynamic research); and to the
neuroimaging capabilities of the proposed PBTC. Respective technologies and capabilities must
be already developed/implemented.

The renewal of
memberships for the fourth and fifth year of project period and the associated
subcontractual funding will be subject to review and competition with other
institutions. During the third year of the project period, the PBTC Operation Center will evaluate the performance of Member Institutions for years 1 and
2. For those initially selected Member Institutions that will be rated in the lower tertile,
membership renewal for years 4 and 5 must be based on
an open competition (with non-member institutions also invited to participate).
Applicants must describe their plans for performance evaluation and procedures
for membership renewal that meet these conditions.

In addition to the
required member institutions (up to 7), the PBTC applicants also have the
option of establishing collaborations with other institutions with similar
capabilities that might be willing to interact with PBTC on a collaborative
basis (i.e., using their own funding outside of the support for the PBTC).

The
Patient Study Research Fund will support the collection of blood and tissue specimens
at the Member Institutions as appropriate for the conduct of correlative
studies. This Fund will also reimburse Member Institutions for the performance
of imaging studies when these are necessary for research purposes and are
included as study endpoints.

The
Biology/Pharmacokinetic Fund will support the relevant laboratory analyses at
the Member Institutions using these specimens.

Beyond the scope that
would be supported by the PBTC award, the PBTC applicants are encouraged to
accommodate expansion of pharmacokinetic and correlative studies through other
sources of funding.

Specific Benchmarks for the PBTC

The specific benchmarks for the PBTC in the 2009
– 2014 funding period are listed below. These benchmarks will be
used by the NCI to determine whether the PBTC has satisfactorily contributed to
NCI’s clinical research program for children with brain tumors.

1) The number of
Phase 1, Phase 2, and pilot clinical trials initiated and successfully
completed (approximately 3-4 per year), which should correspond to an estimated
accrual rate of 100 to 150 patients per year, depending upon the mix of studies
(e.g., Phase 1 versus Phase 2) in any given year;

2) The use of
appropriate clinical trial designs to allow for (a) dose determination for
Phase 2 studies; (b) the determination of the feasibility and tolerability of
new treatment regimens; and (c) the meaningful assessment of clinical activity
in Phase 2 studies;

5) The productive
incorporation of neurosurgical expertise into PBTC-conducted
clinical trials to address important biological and therapeutic
questions for childhood brain cancers;

6) The timely
development of clinical trials protocols and activation of corresponding
clinical trials (defined as per CTEP timeline requirements);

7) The timely
presentation of results at national/international meetings and timely
publication of results in peer reviewed journals;

8) The use of
caBIG-compatible systems for the management of PBTC clinical
and imaging data;

9) The generation
of high quality data (ensured through an effective QA/QC program and by review
of data submitted to CTEP);

10) The establishment
of formal interactions with other brain tumor research programs (e.g., SPORE
grantees and other brain tumor research programs supported through NIH as well
as non-NIH funding sources) to demonstrate the openness of PBTC to scientific
input and scientific collaboration in developing its research program; and

11) The
transitioning of new treatment approaches studied by the PBTC to the
Children’s Oncology Group (COG) Brain Tumor Committee.

All the PBTC applicants
must adopt and incorporate the above listed benchmarks in their applications
(and shape their specific plans accordingly).

In
the cooperative agreement mechanism, the Project Director/Principal
Investigator (PD/PI) retains the primary responsibility and dominant role for
planning, directing, and executing the proposed project, with NIH staff being
substantially involved as a partner with the Principal Investigator, as
described under the Section VI. 2. Administrative
Requirements, "Cooperative Agreement Terms and Conditions of
Award."

2. Funds Available

The estimated amount of funds available for the PBTC program is $2.2 million for
fiscal year 2009 (with the NCI providing 2 million and NINDS 0.2
million) and up to $11.8 million over the planned 5 year project period
(with the total NCI and NINDS contributions of approximately 10.8 and 1.0
million, respectively). Future year amounts will
depend on annual appropriations.

These funds will be used to fund one PBTC award as a
result of this FOA. In addition, contingent on the
availability of funds, the NCI may release during the PBTC project period an
RFA for competitive supplements to expand the scope of the PBTC award by
innovative clinical trials proposed by non-PBTC institutions.

Because the nature
and scope of the proposed research will vary from application to application,
it is anticipated that the size and duration of each award will also vary.
Although the financial plans of the NIH IC(s) provide support for this program,
awards pursuant to this funding opportunity are contingent upon the
availability of funds and the receipt of a sufficient number of meritorious
applications.

Facilities and
administrative (F&A) costs requested by consortium participants are not
included in the direct cost limitation; see NOT-OD-05-004.

Applications must be
prepared using the current PHS 398
research grant application instructions and forms (version 11/2007 or later
if available). Applications must have a D&B Data Universal Numbering System
(DUNS) number as the universal identifier when applying for Federal grants or
cooperative agreements. The D&B number can be obtained by calling (866)
705-5711 or through the web site at http://www.dnb.com/us/.
The D&B number should be entered on line 11 of the face page of the PHS 398
form.

The title and
number of this funding opportunity must be typed in item (box) 2 only of the
face page of the application form and the YES box must be checked.

The applicants must
demonstrate in the application their ability to meet the RESEARCH OBJECTIVES of
the FOA (described in Section II) and the investigator
responsibilities (described in Section VI.2.A.1).

For the PBTC application submitted in response
to this FOA, the standard PHS398 Research Plan (Items 2-5, formerly designed as
Sections A-D) is altered as follows:

The
number of pages has been increased from 25 to 50 pages (the applicant is
encouraged to use the minimum number of pages necessary to clearly and
succinctly describe the research plan). The 50 pages (or fewer if
possible) should be apportioned as desired by the applicant to cover new
Sections 1- 6 (and part of new Section 7), as outlined below.

An additional
page allocation is allowed as expansion of the new Section 7 to describe
the capabilities of the proposed Member Institutions (two pages per institution
maximum) as described in the instructions for Section 7 below.

Other
sections of the PHS398 Research Plan (Items 6-17) remain unmodified.

Section 1: Progress Report (Competing
Continuation Applications) or Relevant Past Performance (New Applicants). In this section, a
competing continuation application must include a progress report for the
current 5-year funding period. New applicants must summarize their past
performance during the preceding 4-5 years, focusing on multi-institutional
clinical trials with direct relevance to the proposed PBTC research
scope. Specific areas to address include, but are not limited to, the
following:

a) Clinical trial protocol development:
A listing of clinical trial protocol development activities during the previous
funding period (or during the past 4-5 years), including letters of intent
(LOIs) submitted, clinical trial protocols submitted, and clinical trials
activated, with timelines for specific steps in the clinical trial protocol
development process.

b) A brief description of clinical
trials (e.g., 0.5 to 1.0 page per trial) that have been initiated during the
prior funding period (or during the past 4-5 years). This summary of each
clinical trial should cover the important aspects of the study (e.g., schedule,
target patient population, patients accrued, etc.) and salient findings (e.g.,
dose levels evaluated and recommended dose for Phase 2 trials, important
adverse events observed, pharmacokinetic findings, and anti-tumor activity
observed). Copies of all clinical trial protocols should be provided as
appendices, along with the most recent Study Reports prepared by the Statistics
and Data Center (or its equivalent for new applicants) for each study. A
table should be included in the Progress Report Section that enumerates patient
accrual by year for each study.

c) Pharmacokinetic and pharmacodynamic
research contributions: A description of the research accomplishments for
pharmacokinetic/pharmacodynamic studies associated with the clinical trials
described above.

d) Neuroimaging
contributions: A description of the neuroimaging studies that have been
incorporated into past clinical trials and the contributions that these
neuroimaging studies have made.

e) Annual accrual to
clinical trials during the previous funding period (or during the past 4-5
years) by gender and ethnicity/race composition should be described in the
PHS398 Inclusion Enrollment Report form.

f) Publications
during the previous funding period (or during the past 4-5 years) should be
listed as per PHS398 instructions.

Section 2: Investigators Qualifications:

A brief
description that highlights the relevant qualifications and experience in
pediatric neuro-oncology clinical research of key personnel, including: the PI
of the proposed PBTC; the Director(s) of the Operations Center and of the
Statistics and Data Center; the Neuroimaging Center Director; and other key personnel providing essential scientific
leadership to the proposed PBTC (e.g., leaders of Scientific or Discipline
Committees), as appropriate.

NOTE: Relevant
qualifications and experience of Member Institution PIs should be highlighted
within the synopses provided for each Member Institution (see Section 7). In addition, note that leaders at
Member Institutions (whether or not designated site PIs) are considered Key
Investigators.

Section 3: Research Strategies and Research
Plans: The
research strategy and plans for the proposed PBTC to develop new treatment
approaches for children with brain tumors through Phase 1, Phase 2, and pilot
clinical trials should be described, including:

The general
approach to study design and research plans for Phase 1, Phase 2, and pilot
clinical trials to evaluate systemically administered new agents, particularly
investigational agents designed to affect specific molecular targets with
direct relevance to the pediatric brain tumor population. For such
agents, describe and document the ability to select patients for study based on
specific molecular characteristics of their brain tumors. Describe
criteria for the prioritization of novel systemically administered agents for
evaluation by the PBTC.

Procedures and
plans for the conduct of correlative laboratory studies should be addressed,
including the incorporation of pharmacokinetic, pharmacodynamic, and
pharmacogenetic endpoints into clinical trials evaluating new agents, as
appropriate. The ability of the proposed PBTC to coordinate the
collection of tumor specimens, biological fluids, and relevant clinical data
and their distribution to the appropriate laboratories or tumor/specimen
repositories (as will be required by specific clinical trials protocols) should
be described.

Research plans
for evaluating agents administered either by the intraventricular or
intrathecal routes;

Plans for
research studies that utilize the specialized neurosurgical expertise required
for the proposed PBTC;

Plans for
studies focused on radiation therapy, including the use of systemically
administered chemotherapy to potentiate the effectiveness of radiation;

Research plans
for developing disease-specific pilot studies for defined pediatric patient
populations (e.g., the population of children with diffuse intrinsic brain stem
gliomas). Applications should include plans during the period of the
award to prioritize new treatment approaches for the patient population with
brain stem glioma based on the molecular characteristics of diffusely infiltrating
tumors arising in the brain stem (e.g., as defined using archival or autopsy
materials). The performance of tumor biopsies at the time of diagnosis as an
element of PBTC clinical trials must be described within the regulatory and
ethical constraints imposed by the Code of Federal Regulations (CFR) Title 45
Part 46 Subpart D (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#subpartd).

Research plans
proposed for the Neuroimaging Center which
include: i) the plans to incorporate imaging endpoints and investigations on
specific imaging research problems into the overall research program of the
PBTC; ii) the availability of adequate post-image storage, processing, and
analysis capabilities to conduct correlative imaging research; and iii) the
plans of the Neuroimaging Center to coordinate
with and engage imagers at each Member Institution to develop and implement
common imaging protocols as appropriate as well as correlative imaging
research.

Procedures and
plans for assuring timely publication of the results of clinical trials and
laboratory studies to be conducted by the proposed PBTC. Describe actions to be
taken when these time lines are not met.

Section 4: Standard Procedures for the
Development of Clinical Trial Protocols. A description of the standard procedures
developed and utilized by
the applicants to support the timely development of Phase 1, Phase 2, and pilot
clinical trials for children with brain tumors. Describe briefly the
procedures listed below and provide benchmarks of their successful
implementation:

Organizational
structure and procedures for coordinating the timely development of clinical
trial protocols, including time lines for the steps in this process and actions
to be taken when these time lines are not met. Templates for clinical trial
protocols that the PBTC applicants use currently should be included as
appendices.

Procedures for
effective interaction and communication involving the leadership of the
proposed PBTC, Study Committees, and Member Institutions to facilitate the
development of clinical trial protocols and conduct of clinical trials in safe
and timely manner.

The
statistical support for the PBTC clinical trials, and the general statistical approach to the design and analysis
of Phase 1, Phase 2, and pilot clinical trials.

Organizational
structure and procedures for data collection and management from multi-institutional Phase 1, Phase 2, and pilot
clinical trials. Include a description of (a) facilities and data management
resources and personnel; (b) procedures for ensuring the technical integrity
and security of the data management systems; (c) procedures for development of data collection forms; and (d) procedures
for data transmittal, data editing, and quality control/verification of
submitted data.

Procedures
for training of Member Institution personnel to maintain their proficiency in
the management of Phase
1, Phase 2, and pilot clinical trials.

The Data and
Safety Monitoring Plan for PBTC (to be included in the Appendices of the
application), which should be consistent with NIH and NCI guidelines for data
monitoring in early phase clinical trials.

Procedures for
timely reporting of all serious and/or unexpected adverse events via (a) the
Adverse Event Expedited Reporting System (AdEERS, http://ctep.cancer.gov/reporting/newadverse_2006.pdf)
for investigational agents for which the status of Investigational New Drug
(IND) has been sponsored by the NCI and (b) sponsor-specified methods for other
agents bearing the IND status.

Procedures to
meet Office for Human Research Protections (OHRP) requirements for the
protection of human subjects, including informed consent, institutional review
board (IRB) review of protocols, and institutional assurances.

Note: Conflict-of-Interest Policy to be used by the proposed PBTC must be
included in the Appendices to the application. This policy and associated
procedures must be consistent with PHS requirements for ensuring that there is
no reasonable expectation that the design, conduct, and/or reporting of
research conducted by the proposed PBTC will be biased by any conflicting
financial interests of an investigator.

Section 7: Member Institutions: Provide two types of
information as defined below.

A. General Policies and Procedures Regarding Member
Institutions. Include
(within the page-limited portion of Research Plan) a description of the
following aspects:

Criteria used to
select Member Institutions;

Procedures for
Institutional Performance Monitoring (addressing, for example, accrual of
adequate number of eligible patients to the PBTC clinical trials, timely
submission of required data, observance of clinical trial protocol
requirements, contributions to clinical trial protocol development and conduct,
authorship in the PBTC publications, and participation in the PBTC
administrative and scientific committees);

Procedures for
responding to inadequate performance and for removing institutions from the
PBTC if performance is not adequate, including evaluation criteria to identify
those institutions rated in the lower tertile of performance by year 2 of the
award;

A mechanism for
replacing the lowest ranking Member Institutions (which must be based on an open
competition with non-member institutions also invited to participate).

Key aspects of
the past performance of Member Institutions summarized in one or more tables to
cover, for example, accrual to Consortium trials by year, enrollment of
ineligible patients and lack of disease measurability when required, timeliness
of data submission, timeliness of report submission for AdEERS [Adverse Event
Expedited Reporting System], compliance with specimen submission, etc.
For new applicants, institutional performance in comparable trials should be
described.

If
applicable, optional collaborations with other institutions with similar
capabilities that might be willing to interact with PBTC and conduct similar
research on a collaborative basis (i.e., using their own funding, outside of
the support for the PBTC).

B. Synopses of Individual Member
Institutions. Provide
a brief description of how each Member Institution meets the criteria for
appropriate research capabilities and for acceptable performance. These
pages do not count towards the 50-page limit for the Research Plan but must not
exceed two pages per Member Institution. The synopses may include, but are
not limited to, the following:

The clinical
and/or basic research experience, training, percentages of effort that key
personnel will devote to the PBTC activities, research competence, and
commitment to the PBTC participation of the institutional (site) PIs (for
example, as evidenced by past clinical research contributions and current
research efforts relating to neuro-oncology drug development). Note that “site PIs” at
individual Member Institutions are considered Key Investigators. Accordingly,
Biographical Sketches must be submitted for each PI as per PHS398 instructions.

Documented
ability to meet the intensive data collection and regulatory requirements
necessary for early phase clinical trials. Institutional data management
resources and plans for utilizing these resources for timely data submission
for the PBTC clinical trials should be described.

Documented
ability to recruit approximately 10 patients per year to Phase 1, Phase 2, and
pilot clinical trials for children with cancer (minimum of five patients
accrued to Phase 1 trials per year).

Availability of
state-of-the-art imaging, such as magnetic resonance imaging (MRI), functional
MRI, magnetic resonance spectroscopy (MRS), and positron emission tomography
(PET). Include a
statement indicating the institutional commitment for utilizing these methodologies in the conduct
of the PBTC studies when such imaging studies are required.

Scientific
expertise (both clinical and laboratory) that is available at the institution
and applicable to the development of new drugs for pediatric oncology. Include
a statement that the institution is willing to utilize this expertise for the
conduct of the PBTC correlative studies (e.g., pharmacokinetic and
pharmacodynamic monitoring or imaging research studies).

Arrangements
that will be available to families of patients who live some distance from the
institution to facilitate participation of these patients in PBTC clinical
trials.

Notes on
Budget: The budget
for the PBTC should include the items listed below. Use the provided cost
estimates for individual categories as guidelines. Deviations from these
estimates are allowable but should be justified.

Scientific
Leadership Commitment: The lead PI designated to be in charge of the overall scientific
direction of PBTC as well as the PI(s) designated to be director(s) of the
Statistics and Data Center and the Operations Center are expected to have
substantive commitment (at least 20% effort) to PBTC activities. Other
PIs may be designated as appropriate, e.g. at the individual Member
Institutions (with a minimum effort commitment of 10%, see below). The PBTC may also provide support
for other scientific leadership positions (e.g., leadership of Scientific and
Discipline Committees) and to Study Chairs, with allocation of funds based on
the scientific contribution of investigators to the PBTC.

Operations Center Costs for Regulatory and
Administrative Activities: Funds should be planned to support the Regulatory and Administration
activities (approximately $300,000 per year) related to overall project
management and coordination, protocol development and implementation, and
QC/QA.

Statistics
and Data Center Support for Data Management and Analysis Activities: Approximately $300,000 per year may
be requested to support data management and analysis, statistical leadership,
support personnel, and information technology support.

Costs for
Member Institutions (Site Support Fund): Allocation of
funds to participating Member Institutions must be planned through
subcontractual arrangements. Funds may be allocated to support
research-related costs at Member Institutions that must be sustained
independent of patient enrollment (e.g., salary support of key personnel
participation of site PI in the PBTC’s Steering Committee and/or other
PBTC activities, IRB submission of protocols, site training program, pharmacy
set-up, site administration, and data collection). Approximately $300,000
to $350,000 is expected to be allocated to support approximately 10% effort of
the site PI and 20-30% effort of a Clinical Research Associate (CRA) for these
activities. Funds should also be provided to sites to support
travel of three to four persons (on average) from each site to attend PBTC
semiannual meetings. In addition to fixed costs, applicants should plan for
approximately $375,000 allotted for “per case” reimbursement to
Member Institutions. This estimate is based upon 125 cases at up to $3,000 per case.

Biology/Pharmacokinetics-Pharmacodynamics
Fund: These funds are to support
laboratory studies (e.g., pharmacokinetic and pharmacodynamic studies)
performed on specimens (e.g., blood, tumor tissue, buccal cells, etc.) obtained
from children enrolled on the PBTC clinical trials. This fund should be
at least $100,000 per year but no more than $300,000 per year.

Patient
Studies Research Fund: These funds are to be allocated to support institutional costs of
research that are not considered “a cost of treatment” by medical
insurers, and therefore are not reimbursed by insurers (e.g., blood and urine
collection and shipping for pharmacokinetic studies, tumor tissue handling and
shipping to the tissue bank or Biopathology Center, and performance of research
imaging studies). This fund should be approximately $300,000 per year.

Neuroimaging Center: Approximately $250,000 is
anticipated to support the Neuroimaging Center to develop
the imaging research plans for PBTC studies (in collaboration with other
radiologists within the PBTC), and to collect, analyze, and archive imaging
data to meet imaging study objectives.

Applications
with Multiple PDs/PIs

When multiple PD/PIs are
proposed, use the Face Page-Continued page to provide items 3a – 3h for
all PD/PIs. NIH requires one PD/PI be designated as the “contact
PD/PI” for all communications between the PD/PIs and the agency. The
contact PD/PI must meet all eligibility requirements for PD/PI status in the
same way as other PD/PIs, but has no special roles or responsibilities within
the project team beyond those mentioned above. The contact PD/PI may be changed
during the project period. The contact PD/PI should be listed in block 3 of
Form Page 1 (the Face Page), with all additional PD/PIs listed on Form Page
1-Continued. When inserting the name of the PD/PI in the header of each
application page, use the name of the “Contact PD/PI, et. al.” The
contact PD/PI must be from the applicant organization if PD/PIs are from more
than one institution.

All individuals designated
as PD/PI must be registered in the eRA Commons and must be assigned the PD/PI
role in that system (other roles such as SO or IAR will not give the PD/PI the
appropriate access to the application records). Each PD/PI must include their
respective eRA Commons ID in the eRA Commons User Name field.

All projects proposing
Multiple PDs/PIs will be required to include a new section describing the
leadership plan approach for the proposed project.

Multiple
PD/PI Leadership Plan: For applications designating multiple PDs/PIs, a new
item of the research plan (item 14 in the November 2007 release of PHS 398
Table of Content), entitled “Multiple PD/PI Leadership Plan” must
be included. A rationale for choosing a multiple PD/PI approach should be
described. The governance and organizational structure of the leadership team
and the research project should be described, and should include communication
plans, process for making decisions on scientific direction, and procedures for
resolving conflicts. The roles and administrative, technical, and
scientific responsibilities for the project or program should be delineated for
the PDs/PIs and other collaborators.

If
budget allocation is planned, the distribution of resources to specific
components of the project or the individual PDs/PIs should be delineated in the
Leadership Plan. In the event of an award, the requested allocations may be
reflected in a footnote on the Notice of Award.

Prospective
applicants are asked to submit a letter of intent that includes the following
information:

Descriptive
title of proposed research;

Name,
address, and telephone number of the PD(s)/PI(s)

Names
of other key personnel;

Participating
institutions; and

Number
and title of this funding opportunity.

Although a letter of
intent is not required, is not binding, and does not enter into the review of a
subsequent application, the information that it contains allows NIH IC staff to
estimate the potential review workload and plan the review.

Applications
must be prepared using the forms found in the PHS 398 instructions for
preparing a research grant application. Submit a signed, typewritten
original of the application, including the checklist, and three signed photocopies in one package to:

Applications must be received on or before the
application receipt date) described above (Section
IV.3.A.). If an application is received after that date, the application
may be delayed in the review process or not reviewed. Upon receipt,
applications will be evaluated for completeness by the CSR and for
responsiveness by the reviewing Institute Incomplete and/or non-responsive
applications will not be reviewed.

The NIH will not
accept any application in response to this funding opportunity that is
essentially the same as one currently pending initial review, unless the
applicant withdraws the pending application. However, when a previously
unfunded application, originally submitted as an investigator-initiated
application, is to be submitted in response to a funding opportunity, it is to
be prepared as a NEW application. That is, the application for the funding
opportunity must not include an Introduction describing the changes and
improvements made, and the text must not be marked to indicate the changes from
the previous unfunded version of the application.

All NIH awards
are subject to the terms and conditions, cost principles, and other
considerations described in the NIH Grants Policy Statement. The Grants Policy
Statement can be found at NIH Grants
Policy Statement.

Pre-award
costs are allowable. A grantee may, at its own risk and without NIH prior
approval, incur obligations and expenditures to cover costs up to 90 days before
the beginning date of the initial budget period of a new or
renewal award if such costs: 1) are necessary to conduct the project,
and 2) would be allowable under the grant, if awarded, without NIH prior
approval. If specific expenditures would otherwise require prior approval, the
grantee must obtain NIH approval before incurring the cost. NIH prior approval
is required for any costs to be incurred more than 90 days before the beginning
date of the initial budget period of a new or renewal award.

The
incurrence of pre-award costs in anticipation of a competing or non-competing
award imposes no obligation on NIH either to make the award or to increase the
amount of the approved budget if an award is made for less than the amount
anticipated and is inadequate to cover the pre-award costs incurred. NIH
expects the grantee to be fully aware that pre-award costs result in borrowing
against future support and that such borrowing must not impair the grantee's
ability to accomplish the project objectives in the approved time frame or in
any way adversely affect the conduct of the project (see NIH Grants Policy Statement http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm).

6. Other
Submission Requirements and Information

Awardees
must agree to the "Cooperative Agreement Terms and Conditions of
Award" in Section VI.2.A "Award Administration Information."

Appendix
Materials

All paper PHS 398 applications submitted for May 25, 2008, and
subsequent due dates must provide
appendix material on CD only, and include five identical CDs in the same
package with the application. Paper applications submitted for due dates
prior to May 25, 2008, may voluntarily provide the appendix on five identical
CDs; if submitting CDs it is not necessary to include a paper appendix (seehttp://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-031.html).

Do
not use the Appendix to circumvent the page limitations of the Research Plan
component. An application that does not observe the required page limitations
may be delayed in the review process.

Resource Sharing
Plan(s)

NIH considers the sharing of unique research resources
developed through NIH-sponsored research an important means to enhance the
value of, and advance research. When resources have been developed with NIH
funds and the associated research findings published or provided to NIH, it is
important that they be made readily available for research purposes to
qualified individuals within the scientific community. If the final data/resources are not amenable to sharing,
this must be explained in Resource Sharing section of the application. See http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm.

(b) Sharing Model Organisms: Regardless of
the amount requested, all applications where the development of model organisms
is anticipated are expectedto include a description of a
specific plan for sharing and distributing unique model organisms and related
resources, or state appropriate reasons why such sharing is restricted or not
possible. See Sharing
Model Organisms Policy and NIH
Guide NOT-OD-04-042.

(c) Genome-Wide Association Studies (GWAS): Regardless of the amount requested,
applicants seeking funding for a genome-wide association study are
expected to provide a plan for submission of GWAS data to the NIH-designatedGWAS data repository, or provide an appropriate explanation why
submission to the repository is not possible. A genome-wide association
study is defined as any study of genetic variation across the entire genome
that is designed to identify genetic associations with observable traits (such
as blood pressure or weight) or the presence or absence of a disease or
condition. For further information see Policy for Sharing of Data
Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088, and http://grants.nih.gov/grants/gwas/.

Section
V. Application Review Information

1. Criteria

Only the review
criteria described below will be considered in the review process.

2. Review and Selection Process

Applications that are complete and
responsive to the FOA will be evaluated for scientific and technical merit by an
appropriate peer review group convened by National Cancer
Institute and
in accordance with NIH peer review procedures (http://grants1.nih.gov/grants/peer/),
using the review criteria stated below.

As part of the scientific peer
review, all applications will:

Undergo a
selection process in which only those applications deemed to have the highest
scientific and technical merit, generally the top half of applications under
review, will be discussed and assigned a priority score;

Receive a
written critique; and

Receive a second
level of review by NCI’s National Cancer Advisory Board.

The
following will be considered in making funding decisions:

Scientific and
technical merit of the proposed project as determined by peer review;

Availability of
funds; and

Relevance of the
proposed project to program priorities.

The
goals of NIH supported research are to advance our understanding of biological
systems, to improve the control of disease, and to enhance health. In their
written critiques, reviewers will be asked to comment on each of the following
criteria in order to judge the likelihood that the proposed research will have
a substantial impact on the pursuit of these goals. Each of these criteria will
be addressed and considered in assigning the overall score, weighting them as
appropriate for each application. Note that an application does not need to be
strong in all categories to be judged likely to have major scientific impact
and thus deserve a meritorious priority score. For example, an investigator may
propose to carry out important work that by its nature is not innovative but is
essential to move a field forward. The following general (NIH-wide) criteria appended with
aspects specific to this FOA will be used.

Significance:Does this study address an important problem? If the
aims of the application are achieved, how will scientific knowledge or clinical
practice be advanced? What will be the effect of these studies on the concepts,
methods, technologies, treatments, services, or preventative interventions that
drive this field?

Approach:Are the conceptual or clinical framework, design,
methods, and analyses adequately developed, well integrated, well reasoned, and
appropriate to the aims of the project? Does the applicant acknowledge
potential problem areas and consider alternative tactics? For applications
designating multiple PDs/PIs, is the leadership approach, including the
designated roles and responsibilities, governance, and organizational
structure, consistent with and justified by the aims of the project and the
expertise of each of the PDs/PIs?In addition, specific to this FOA -- Research Strategies and Research
Plans:

Does the past
performance of the applicant and its proposed Member Institutions in the
relevant areas support the applicants’ ability to collaboratively
implement its projected research plans for evaluating new treatment approaches
for children with brain tumors and for associated studies required by this
FOA?

Has the
applicant team developed and conducted of multi-institutional clinical trials
that required specialized expertise (e.g., neurosurgical, neuroimaging, etc.)
and that included, the incorporation of pharmacodynamic/pharmacokinetic,
neuroimaging, and other specialized endpoints?

Do the
applicants’ plans for clinical trials demonstrate an appropriate
understanding of research opportunities and challenges in pediatric drug
development including the issues associated with the evaluation of molecularly
targeted agents?

Are the proposed
methodologies available and appropriate for exploiting these opportunities in
children with brain tumors?

Are the plans
for incorporating pharmacokinetic, pharmacodynamic, and pharmacogenetic
endpoints into its clinical trials appropriate and based on state-of-the-art
approaches?

Do the research
plans for specific patient populations (e.g., patients with brain stem glioma)
address clinically important problems using well reasoned study designs?

Do the research
plans for evaluating agents administered either by the intraventricular or
intrathecal routes address clinically important problems using appropriate
study designs?

Are the research
plans for incorporating neuroimaging objectives into the PBTC’s overall
research program appropriate?

Are there
adequate plans for the interactions between the proposed PBTC and other NIH neuroimaging initiatives and networks?

Are radiation therapy and neurosurgery appropriately
incorporated into the applicants’ research program, both as research
objectives and as requisite therapeutic modalities?

Have the
applicants developed proactive plans for communication and collaboration with
other NCI/NIH funded as well as privately supported researchers/groups working
in the field?

Are the roles
and tasks of the major leadership and scientific committees clearly articulated
and developed? Are these committees and their described interactions and
roles appropriate for effective prioritization of PBTC resources?

Innovation: Is the project original and innovative? For example: Does
the project challenge existing paradigms or clinical practice; address an
innovative hypothesis or critical barrier to progress in the field? Does the
project develop or employ novel concepts, approaches, methodologies, tools, or
technologies for this area?

In addition, specific to this FOA

Do the
applicants propose novel or improved ways and/or methods to enhance or better
serve the goals of the PBTC?

Investigators:Are the PD/PI(s) and other key personnel
appropriately trained and well suited to carry out this work? Is the work
proposed appropriate to the experience level of the principal investigator and
other researchers? Does the PD/PI(s) and investigative team bring complementary
and integrated expertise to the project (if applicable)?

In
addition, specific to this FOA

Are the
qualifications, expertise, and experience of the lead PI, site PIs, and other
PBTC clinical scientists appropriate to provide adequate scientific leadership
for developing and implementing the PBTC’s Phase 1, Phase 2, and pilot
clinical trials?

Are there
sufficient and appropriately experienced personnel with the skills needed to
develop, implement, and analyze Phase 1, Phase 2, and pilot clinical trials?

Do the key
investigators and support personnel have the needed experience in the
collection, management and analysis of data from multi-institutional clinical
trials, including procedures for ensuring the technical integrity and security
of the collected data?

Do the
applicants have sufficient radiologic expertise to guide innovative use of
imaging in the PBTC’s clinical trials?

Environment: Does the scientific environment in which the work
will be done contribute to the probability of success? Do the proposed studies
benefit from unique features of the scientific environment, or subject
populations, or employ useful collaborative arrangements? Is there evidence of
institutional support?

In addition to the above NIH-wide review criteria, the
following FOA-specific criteria will be applied to applications

Clinical Trial Protocol Development:

Are the
procedures described in the application appropriate for the timely development
of the PBTC’s Phase 1, Phase 2, and pilot clinical trials?

Data Management and Analysis and Quality
Assurance:

Does the PBTC
applicant have sufficient statistical support and utilize appropriate
statistical design approaches for Phase 1, Phase 2, and pilot clinical trials?

Does the
application adequately demonstrate experience of the applicants in the
collection, management, and analysis of data from multi-institutional clinical
trials, including procedures for ensuring the technical integrity and security
of its clinical trials data?

Does the
application demonstrate adequate procedures to collect, monitor, and analyze
the data and assure the safety of patients/participants in multi-institutional
clinical trials?

Does the
application adequately describe appropriate procedures for quality control and
quality assurance for multi-institutional clinical trials data?

Are there
appropriate and adequate mechanisms for the periodic review of quality control,
quality assurance, data management procedures, safety monitoring (including the
procedures for the data safety and monitoring committees and on-site auditing
programs)?

Does the PBTC
applicant describe appropriate training to maintain
the proficiency of Member Institution personnel in the successful management of its Phase 1, Phase 2, and pilot clinical trials?

Are procedures
for timely reporting of data from PBTC clinical trials to CTEP using the
Clinical Data Update System (CDUS) sufficient to ensure the timely reporting of
reliable clinical trials data?

Is there
sufficient attention paid to quality control of the image acquisition and
collection from member sites?

Regulatory Compliance:

Are there
acceptable procedures described for addressing regulatory compliance in the
context of multi-institutional clinical trials?

Will the
proposed PBTC have suitable procedures for timely reporting of serious and
unexpected adverse events during clinical trials using investigational agents?

Are adequate
processes described for complying with CTEP requirements for investigator
registration and drug accountability, and for complying with the PHS COI
requirements?

Member Institutions:

Are the
institutions that will comprise the proposed PBTC qualified, in terms of
experience and capabilities, for participating in the PBTC’s early phase
clinical trials?

Have the
applicants adopted appropriate criteria for the selection of Member
Institutions and for monitoring the adequacy of Member Institution performance
in an ongoing manner?

2. A.
Additional Review Criteria

In addition to the
above criteria, the following items will continue to be considered in the
determination of scientific merit and the rating:

Protection of Human Subjects from Research Risk: The involvement of human
subjects and protections from research risk relating to their participation in
the proposed research will be assessed (see the Research Plan section on Human
Subjects in the PHS 398 instructions).

Inclusion
of Women, Minorities and Children in Research: The adequacy of plans to
include subjects from both genders, all racial and ethnic groups (and
subgroups), and children as appropriate for the scientific goals of the
research will be assessed. Plans for the recruitment and retention of subjects
will also be evaluated (see the Research Plan section on Human Subjects in the
PHS 398 instructions).

Care
and Use of Vertebrate Animals in Research: If vertebrate animals are to
be used in the project, the five points described in the Vertebrate Animals
section of the Research Plan will be assessed.

Biohazards: If materials or procedures
are proposed that are potentially hazardous to research personnel and/or the
environment, determine if the proposed protection is adequate.

2. B. Additional Review
Considerations

Budget: The reasonableness of the
proposed budget and the requested period of support in relation to the proposed
research. The priority score should not be affected by the evaluation of the
budget.

2. C.
Resource Sharing Plan(s)

When relevant, reviewers will be instructed to comment
on the reasonableness of the following Resource Sharing Plans, or the rationale
for not sharing the following types of resources. However, reviewers will not
factor the proposed resource sharing plan(s) into the determination of
scientific merit or priority score, unless noted otherwise in the FOA.
Program staff within the NIH IC will be responsible for monitoring the resource
sharing.

A
formal notification in the form of a Notice of Award (NoA) will be
provided to the applicant organization. The NoA signed by the grants management
officer is the authorizing document. Once all administrative and programmatic
issues have been resolved, the NoA will be generated via email notification
from the awarding component to the grantee business official (designated in
item 12 on the Application Face Page). If a grantee is not email enabled, a hard
copy of the NoA will be mailed to the business official.

Selection of an application for award is not an
authorization to begin performance. Any costs incurred before receipt of the
NoA are at the recipient's risk. These costs may be reimbursed only to the
extent considered allowable pre-award costs. See Also Section
IV.5. Funding Restrictions.

The
following Terms and Conditions will be incorporated into the award statement
and will be provided to the Principal Investigator as well as to the appropriate
institutional official, at the time of award.

2. A. Cooperative
Agreement Terms and Conditions of Award

The following special
terms of award are in addition to, and not in lieu of, otherwise applicable OMB
administrative guidelines, U.S. Department of Health and Human Services (DHHS)
grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is
applicable when State and local Governments are eligible to apply), and other
HHS, PHS, and NIH grant administration policies.

The administrative and
funding instrument used for this program will be the cooperative agreement an
"assistance" mechanism (rather than an "acquisition"
mechanism), in which substantial NIH programmatic involvement with the awardees
is anticipated during the performance of the activities. Under the cooperative
agreement, the NIH purpose is to support and stimulate the recipients'
activities by involvement in and otherwise working jointly with the award
recipients in a partnership role; it is not to assume direction, prime responsibility,
or a dominant role in the activities. Consistent with this concept, the
dominant role and prime responsibility resides with the awardees for the
project as a whole, although specific tasks and activities may be shared among
the awardees and the NIH as defined below.

Throughout these Terms and
Conditions of Award, “PBTC” refers to the organizational structure
which is composed of the PBTC PI and other key personnel, the Operations Center, the Statistics and Data Center, and Member Institutions, all of whom agree
to collaborate on research goals of the PBTC.

The PBTC is responsible for developing
the details of its clinical and laboratory research program, including definition
of objectives and approaches, planning, implementation, analysis,
interpretations and conclusions of studies, and publication of results.
The PBTC will continue to develop Phase 1, Phase 2, and pilot clinical trial
protocols in accord with the research interests, abilities and goals of the
PBTC, and submit these protocols to CTEP for review prior to their
implementation. Specific Rights and Responsibilities for the Operations Center, Statistics and Data Center, Member Institutions, and the Imaging Center are described below.

The
following documents (and any subsequent modification to them) are hereby
incorporated by reference as terms of award. These documents describe the
programmatic responsibilities for the conduct of the research supported by this
cooperative agreement.

INVESTIGATOR'S
HANDBOOK, a Manual for Participants in Clinical Trials of Investigational
Agents Sponsored by the Division of Cancer Treatment and Diagnosis (DCTD),
National Cancer Institute (http://ctep.cancer.gov/handbook/);
and

The
Operations Center and the Statistics and Data Center are responsible for
coordinating the development of clinical trial protocols, submission of these
protocols for review and approval, study conduct (including central data
collection and analysis), quality assurance/quality control and study
monitoring, protocol amendments/status changes, adherence to requirements
regarding investigational drug management and federally mandated regulations
and protocol and performance reporting. Specific responsibilities are
listed below.

1) Organizational Structure and
Standard Operating Procedures (SOPs): The Operations Center, with the
guidance of the PI designated as its director, the lead PI (if different) and
Steering Committee, are responsible for development and maintenance of an
organizational structure and Standard Operating Procedures for the PBTC.

2) Clinical Trial Protocol Development:
It is the responsibility of the PBTC to develop the details of the research
design, including definition of objectives and approaches, planning,
implementation, analysis, interpretations and conclusions of studies, and
publication of results. The Operations Center is responsible, in
accordance with the PBTC’s SOPs, for the preparation and implementation
of procedures for development and submission of PBTC clinical trial protocols
to the CTEP Protocol and Information Office (PIO) in a timely fashion for
review and approval by NCI.

b) Submission of PBTC clinical trial protocols
for review and approval by NCI should be preceded by a written Letter of Intent
(LOI) to the CTEP LOI Coordinator declaring interest in conducting a particular
study. LOIs should be submitted using the LOI template (http://ctep.info.nih.gov/guidelines/index.html).

c) The Operations Center is responsible
for communicating the results of the CTEP Protocol Review Committee to relevant
PBTC Committees and PBTC members.

d) The PBTC will not expend NCI funds
to conduct any study disapproved by CTEP unless CTEP's disapproval has been
modified by the arbitration process (see Section VI.2.A.4 Arbitration Process).

e) All clinical trials utilizing
NCI-sponsored investigational agents shall be conducted in accordance with the
terms of the “Intellectual Property Option to Collaborators” (http://ctep.info.nih.gov/industry/ipo.html)
and the NCI Standard Protocol Language for Cooperative Research and Development
Agreements (CRADAs) and Clinical Trial Agreements (CTAs).

f) The PBTC’s
SOPs should include timelines for the steps involved in the development of
LOIs, Concept Proposals, and clinical trial protocols, and should include
mechanisms for monitoring the performance of the Operations Center and PBTC members in meeting these time lines. The PBTC’s SOPs should also
include corrective action plans outlining the steps to be taken when these time
lines are not met. Data concerning the PBTC’s performance in
meeting timelines for protocol development should be provided in the Annual
Progress Report.

3) Study Monitoring: The PBTC must
follow the general guidelines for study monitoring for CTEP-sponsored trials as
described at http://ctep.info.nih.gov/monitoring/section2.html#2.2.2. The PBTC is responsible for assuring accurate and timely monitoring
of the progress of each study, and therefore must have standard procedures for
timely data collection and data management consistent with the intensive data
requirements and the need for rapid reporting necessary for Phase 1, Phase 2,
and pilot clinical trials. Standard procedures include (but are not
necessarily limited to):

a) Precise tracking of patient accrual
and adherence to accrual goals defined by clinical trial protocol-defined
accrual goals. If the PBTC wishes to continue accrual to a study beyond
the total accrual goal for eligible and ineligible patients specified in the
clinical trial protocol, the PBTC must seek approval from CTEP prior to
continuing patient accrual.

b) Procedures for assigning dose level
(for Phase 1/dose escalation studies) at the time a new patient is enrolled in
a study, and assuring that the required observation period has elapsed before
beginning a higher dose level.

e) Adequate measures to ensure timely
submission of clinical trials data(e.g., adverse events, anticancer
response, etc.) from Member Institutions. These measures should include
procedures for monitoring compliance with PBTC’s guidelines for data
timeliness on an institution and a study basis, including summary reports of
data submission timeliness to be used for Institutional Performance Review and
to be used for study monitoring (e.g., as specified by the Data and Safety
Monitoring Plan). These summary reports should also be included in the
Annual Progress Report.

f) Rapid reporting
of treatment-related morbidity information and measures to ensure communication
of this information to all relevant parties. For investigational agents
sponsored by the NCI, this involves reporting to the Investigational Drug Branch
(IDB), CTEP, via the Adverse Event Expedited Reporting System (AdEERS)
according to CTEP guidelines specified in each protocol (http://ctep.info.nih.gov/reporting/adeers.html).

g) Preparation of study monitoring
reports describing patient accrual and demographics, data timeliness, toxicity,
and other items as appropriate. Examples of study monitoring reports include
reports prepared for study chairs, the semiannual reports for PBTC meeting agendas,
and reports as required to comply with the PBTC’s Data and Safety
Monitoring Plan.

h) Adequate policies and procedures for
closure of studies. If the PBTC wishes to close accrual to a study prior
to meeting the initially established accrual goal, the interim results and
other documentation should be made available to NCI staff for review and
concurrence prior to implementation of the decision. It is recommended
that statistical guidelines for early closure be presented as explicitly as
possible in the clinical trial protocol in order to facilitate these
decisions. In the event that the study is recommended for early closure
for safety reasons, procedures in the Data and Safety Monitoring Plan regarding
notification of CTEP must be followed.

4) Data Management Policies and
Practices: The responsibilities of the Statistics and Data Center for data management related to study monitoring include:

b) Incorporating security features
consistent with the guidelines of the U.S. DHHS;

c) Implementing procedures for backing
up the PBTC’s clinical and administrative data, including intermittent
duplication of the database with storage at a remote facility;

d) Protecting patient confidentiality
at all steps in the submission and analysis of clinical trials data and
ensuring the technical integrity and security of the data management systems;
and

e) Providing NCI in a timely manner,
upon the request of the Grants Management Officer, true copies of data files
and supporting documentation for all NCI-supported protocols that have a
major impact on patterns of care, as determined by the NCI.

5) Quality Control of PBTC Clinical
Trials: Quality Control and Quality Assurance (QC/QA) Programs are inherently
linked. The Clinical Trials Monitoring Branch (CTMB) of CTEP provides
direct oversight of NCI-sponsored Consortia and Cooperative Group QC/QA
programs. The PBTC is responsible for establishing and implementing
mechanisms to assure the accuracy and reliability of its clinical trials
data. Quality control is a complex topic spanning the entire range of
diagnostic and therapeutic modalities employed by the PBTC. Key items
that should be addressed concerning quality control procedures include:

a) Institutional performance
evaluations. Performance factors to be considered include:

i) Accrual of
adequate number of eligible patients onto PBTC trials;

ii) Timely and accurate submission of
required data;

iii) Rigorous adherence to clinical trial
protocol requirements;

iv) Participation in study development
and in timely publication of study findings;

v) Participation in
PBTC administrative and scientific committees and/or other PBTC activities; and

b) Procedures for placing Member
Institutions on probation for inadequate performance and for removing such
institutions from the PBTC if performance is not adequate during the
probationary period or at any time that the institution (or participating site)
does not meet PBTC standards for institutional performance.

c) Educational functions that address
data collection, data management, and overall data quality. These aspects
include, but are not limited to, the following elements:

i) Training for new
CRAs in the PBTC’s data submission policies and ongoing training for all
CRAs concerning changes to PBTC procedures and instructions for data submission
in new protocols;

ii) Instruction for Study Chairs on
their responsibilities for study monitoring;

iii) Instruction for Member Institution
Principal Investigators and all members at participating sites on their
responsibilities in complying with the PBTC’s SOPs and Federal
regulations at their institution; and

iv) Training/guidance should also be
provided to all participants on how to comply with NCI/NIH policies and
procedures (e.g., Ethics, COI, etc.) in addition to the policies and procedures
of other governmental agencies important to the conduct of clinical trials
(e.g., Office for Human Research Protections, FDA).

d) Procedures for central review of
major elements that impact on the outcome of clinical trials. This will
include central review of claimed responses and adequacy of imaging studies
submitted by member institutions, central review of submitted data with
determination of protocol compliance in dose administration and dosage
modification, and additional review as necessary.

e) On-site Auditing: The PBTC’s on-site monitoring program will be
coordinated with the Clinical Trials Monitoring Branch (CTMB) of CTEP. As a sponsor for investigational
agents and the funding agency for other cancer clinical trials, FDA regulations
require Division of Cancer Treatment and Diagnosis (DCTD) to maintain a
monitoring program. The on-site audit will address issues of data verification, protocol
compliance, compliance with regulatory requirements for the protection of human
subjects and investigational agent accountability. The PBTC is responsible for
maintaining its on-site auditing program in compliance with the Clinical
Trials Monitoring Branch (CTMB, CTEP) guidelines (http://ctep.info.nih.gov/monitoring/guidelines.html)
and for submitting the results of audits to the NCI in accordance with the
guidelines. In
the event that the NCI determines that a PBTC Member Institution failed to
comply adequately with NCI guidelines for conduct of clinical trials, the
accrual of new patients to PBTC protocols at the affected institution shall be
suspended immediately upon notice of the NCI determination. The
suspension will remain in effect until the PBTC conducts the required audit and
the audit report or remedial action is accepted by the NCI. The Operations Center will be responsible for notifying any affected participating institution
of the suspension. During the suspension period, no funds from this award
may be provided to the participating institution for new accruals, and no
charges to the award for new accruals will be permitted.

6) Timely reporting of data to CTEP
using the Clinical Data Update System (CDUS).

b) For clinical trials that do not use
NCI-sponsored investigational agents, reporting to CTEP will generally use the
CDUS Abbreviated procedures (demographic data only).

7) Publications: Timely publication of
major findings is central to the PBTC’s mission and is a primary means by
which the PBTC’s accomplishments can be evaluated.

a) The PBTC will have timelines for the
development of abstracts for meeting presentations and manuscripts for
submission for publication in scientific journals based on its clinical trials
and should have mechanisms for monitoring the performance of the PBTC’s
components in meeting these timelines. Corrective action plans will be
implemented when these timelines are not met.

b) Publication or oral presentation of
work conducted under the PBTC’s Cooperative Agreement requires
appropriate acknowledgment of NCI support.

c) For investigations using an agent
supplied under a CRADA or CTA, the NCI pharmaceutical collaborator will have an
opportunity to review manuscript drafts prior to their submission for
publication as per the NCI Standard Protocol Language for CRADAs and
CTAs. The NCI will have access to all data generated under this
cooperative agreement and may periodically review the data. The awardee
will retain custody and primary rights to the data consistent with current
DHHS, PHS, and NIH policies.

8) PBTC Meetings: The Operations Center is responsible for the organization of semiannual meetings to review
the PBTC’s progress, establish priorities, and plan future
activities. Additional meetings between PBTC members and meetings with
NCI staff may be held as needed. Relevant responsibilities for meeting
organization include:

a) Arranging for appropriate meeting
space and accommodations for attendees;

b) Developing and distributing meeting
agendas;

c) Providing the Report of Studies to
include information detailing patient accrual and demographics, data
timeliness, toxicity experienced by study participants, and other items (e.g.,
outcome data) as appropriate. The Operations Center and Statistics and Data Center are responsible for ensuring that copies of the Report (electronic and/or hard
copy) are distributed to PBTC members and NCI program staff.

d) Preparing summaries as appropriate
after each meeting to be sent to PBTC members and NCI program staff.

9) PBTC Communications: The Operations Center must establish routine electronic communication with Member Institutions
to facilitate clinical trial protocol development and study monitoring and to
facilitate the work of the PBTC’s Study and Scientific Committees.
Relevant communication methods include web site postings, e-mail, teleconferences,
and web/video conferences.

10) Compliance with Federal Regulations
Concerning Clinical Research: The PI and Operations Center will be responsible
for ensuring that the PBTC is in compliance with all applicable federal
regulations concerning the conduct of human subjects research. Policies
and guidelines to be addressed include:

a) OHRP Assurances: The Operations Center must assure that each participating site has a current, approved
assurance on file with OHRP.

b) IRB Review of PBTC Protocols: The Operations Center must assure that each PBTC clinical trial protocol is reviewed and
approved by each Member Institution’s IRB prior to patient entry, and
must ensure that each clinical trial protocol undergoes continuing review no
less than once per year by the IRB so long as the clinical trial is active.

d) IRB Review of the Operations Center
and Statistics and Data Center (http://www.hhs.gov/ohrp/humansubjects/assurance/engage.htm):
An IRB should determine and document that the Operations Center and Statistics
and Data Center have sufficient mechanisms in place to ensure that (i)
management, data analysis, and Data Safety and Monitoring (DSM) systems are
adequate, given the nature of the research involved; (ii) sample protocols and
informed consent documents are developed and distributed to each collaborating
institution; (iii) each collaborating institution holds an applicable
OHRP-approved Assurance; (iv) each clinical trial protocol is reviewed and
approved by the IRB at the collaborating institution prior to the enrollment of
subjects; (v) any substantive modification by the collaborating institution of
sample consent information related to risks or alternative procedures is
appropriately justified; and (vi) informed consent is obtained from each
subject in compliance with DHHS regulations.

f) Adverse Event
Reporting: The Operations Center is responsible for assuring timely
reporting of all serious and/or unexpected adverse events. Adverse events
should be reported using the Common Terminology Criteria for Adverse Events
(CTCAE), which is the NCI’s standard language for reporting adverse
events in clinical trials (http://ctep.cancer.gov/reporting/ctc.html).
For investigational agents sponsored by the NCI, this involves reporting to the
Investigational Drug Branch (IDB), CTEP, via the Adverse Event Expedited
Reporting System (AdEERS) according to CTEP guidelines specified in each
clinical trial protocol (http://ctep.info.nih.gov/reporting/adeers.html).

g) Assuring that the PBTC is in
compliance with CTEP requirements described in the DCTD Investigators' Handbook
for storage and accounting for investigational agents (including NCI/DHHS Drug
Accountability Records [DAR] procedures), and is in compliance with FDA requirements
for investigational agents.

11) Managing and coordinating the
acquisition and shipping of protocol-specified tumor specimens and
biological fluids (with relevant clinical data) to the appropriate laboratories
for testing and to a tumor/specimen repository for storage of specimens for
future correlative laboratory studies.

12) The Operations Center will be responsible for establishing a COI Policy for the Group. This
policy should ensure that there is no reasonable expectation that the design,
conduct, or reporting of research conducted by the Group will be biased by any
conflicting financial interest of an investigator. The policy should be
in compliance with the general policies of the NCI and the NIH.

13) Fiscal management of the PBTC,
including:

a) Establishment of consortium
arrangements with Member Institutions to support PBTC-related activities at
each Member Institution;

b) Administration of the
Biology/Pharmacokinetics Fund, including the process for selecting laboratories
to perform specific studies (a competitive process is encouraged when
feasible); and

c) Distribution of funds from the
Patient Studies Research Fund to member institutions to support special
clinical research costs for patients accrued onto PBTC clinical trials.
Funds will be disbursed on a capitation basis upon documentation that the
test(s) have been performed. It is anticipated that for each PBTC
protocol, the capitation formula for institutional reimbursement required to
offset specific research expenses will be reviewed and approved by the Steering
Committee.

14) Submission of annual progress
reports to the NCI that describe activities and accomplishments during the
previous year of the PBTC. The report will use the PHS 2590 and include:

a) A summary of the overall performance
of the Operations Center and Statistics and Data Center in meeting their
responsibilities to the PBTC for clinical trial protocol development, study
monitoring, and complying with Federal regulations;

b) Summary data on performance of each
PBTC Member Institution, including clinical trial accrual, quality and
timeliness of submitted data, and involvement in clinical trial protocol
development activities; and

c) Research plans, changes in
procedures and/or staff, and the proposed budget for the coming year.

15) Procedures to allow non-PBTC
institutions to participate in the development and conduct of PBTC trials in
those limited situations in which an institution has distinctive expertise or
capabilities that would contribute to successful conduct of a PBTC study.

16) The PBTC will be responsible for conducting a competition in year 3 of the project period
in which those institutions
rated in the lower tertile of performance in the first two years of the award
must compete with non-PBTC institutions to maintain their position in the
PBTC. The PBTC must submit a specific plan for recompetition of this
subset of its member institutions to CTEP by the end of year 2 of the project
period. Following approval of the plan by CTEP, the PBTC will conduct the recompetition process in year 3.

17) Contingent on the availability of
funds, the NCI may release during the PBTC project period an RFA for
competitive supplements to expand the scope of the PBTC award by innovative
clinical trials conducted in non-PBTC institutions. The PBTC will be responsible
for identifying appropriate candidate non-PBTC institutions and working jointly
with them to prepare applications for such competitive supplements. These
applications will undergo regular NIH peer review process by an NCI-managed
peer review committee. Supplemental funds will be awarded only if one or more
of the applications (and the proposals within them) are determined to be of
sufficiently high scientific merit through peer review and through the
NCI’s programmatic decision-making process. If one or more
supplements is/are funded, then PBTC would make subcontract(s) to the selected
non-member institutions.

Responsibilities
of Member Institution:

1) Participation of Member Institution
investigators in PBTC activities, as evidenced by the following:

a) Offering participation in PBTC
studies to eligible patients and entering sufficient number of patients to meet
accrual targets;

i) Serving as
clinical trial protocol Chairs or as members of protocol study teams;

ii) Participating in the Scientific and
Administrative Committees needed to support the PBTC’s research
objectives;

c) Participation in meetings:
Appropriately participating in the semiannual meetings of the PBTC (and
in other meetings as deemed necessary for performance of PBTC activities);

d) Following the PBTC’s SOPs for
the conduct of clinical research.

2) Implementing the core data
collection method and strategy of the PBTC: It is the responsibility of each
Member Institution to ensure that the procedures for data submission for each
PBTC clinical trial protocol are understood by investigators at the site and
that protocol-specified data are submitted accurately and in a timely
manner to the Statistics and Data Center.

3) Complying with mechanisms for
quality assurance and quality control of therapeutic and diagnostic modalities
employed in PBTC trials. Institutional responsibilities for quality control
include, but are not limited to, the following:

b) Imaging: Submission of appropriate
imaging studies to allow central review of claimed responses and adequacy of
imaging and to allow the imaging research objectives of the PBTC to be met.

4) On-site Auditing:
Participation in the on-site monitoring program established by the PBTC.

5) Human Subjects Protection: Each
institution must comply with OHRP and FDA regulations concerning protection of
human subjects. Member Institutions must implement the procedures established
by the PBTC to meet OHRP and FDA requirements for the protection of human
subjects.

6) Adverse Event Reporting:
Implementing the procedures established by the PBTC for assuring timely
reporting of all serious and/or unexpected adverse events.

7) Investigational agent
responsibilities: Implementing the procedures established by the PBTC for
assuring that PBTC investigators performing clinical trials involving DCTD
Investigational Agents are NCI registered investigators (Form 1572) and for
assuring that the Member Institution PBTC complies with CTEP requirements
described in the DCTD Investigators' Handbook for storage and accounting for
investigational agents (including NCI/DHHS Drug Accountability Records [DAR]
procedures), and is in compliance with FDA requirements for investigational
agents.

8) Submission of specimens: Acquisition
and submission of protocol-specified tumor specimens, biological fluids
and relevant clinical data to the appropriate laboratories where these
specimens will be tested or stored for future studies.

9) Serving as a resource for the
conduct of protocol-specified laboratory projects (e.g., pharmacokinetic
studies, tumor biology studies). The PBTC Steering Committee will
establish a process for the selection of the laboratories to perform these
studies. These projects may be supported using the
Biology/Pharmacokinetics Funds of the PBTC or by independent funding.

10) Participating in PBTC procedures for
the timely publication of major findings.

11) Conflict of Interest: Complying with
the Conflict of Interest Policy of the PBTC to ensure that there is no
reasonable expectation that the design, conduct, or reporting of research
conducted by the PBTC will be biased by any conflicting financial interest of
an investigator.

Responsibilities
of Imaging Center:

1) Developing a correlative imaging
research program, in collaboration with other PBTC investigators, which
directly contributes to the PBTC’s ability to incorporate imaging
endpoints into its overall clinical research program.

2) Directing the primary analysis of
the PBTC’s imaging studies and serving as a repository for research
imaging studies.

3) Serving as a coordinator for imagers
at Member Institutions sites to facilitate common imaging protocols as
appropriate.

4) Serving as a resource for the PBTC
Steering Committee.

5) Participating in the development of
clinical trial protocols, particularly for imaging components.

6) Participating in the Scientific and
Administrative Committees needed to support the PBTC’s research
objectives.

7) Participation in meetings:
Appropriately participating in the semi-annual meetings of the PBTC (and in
other meetings as deemed necessary for performance of PBTC activities).

8) Human Subjects Protection: It is
anticipated that the Imaging Center will be retrospectively reviewing images
without patient identifiers. However, as applicable the Center must be in
compliance with OHRP and FDA regulations concerning protection of human
subjects.

9) Participating in PBTC procedures for
the timely publication of major findings.

10) Collaborating, as appropriate, on
problems of mutual interest with the Imaging Center of the NCI Adult Brain
Tumor Consortium and with other NIH imaging networks.

Awardees
will retain custody of and have primary rights to the data and software
developed under these awards, subject to Government rights of access consistent
with current DHHS, PHS, and NIH policies.

2.A.2. NIH
Responsibilities

The NCI and
NINDS will coordinate and facilitate various activities of the PBTC. The NCI and NINDS staff
members will have substantial programmatic involvement that is above and beyond
the normal stewardship role in awards. The NCI Program Director serving as Project
Scientist will be the main NCI contact for all facets of the scientific
interaction with the awardees and will provide oversight and advice to the
awardee on specific scientific and/or analytic issues in addition to
programmatic issues. The NINDS Program Director serving as Project Coordinator
will also provide oversight, advice, and coordination of efforts with
NINDS-supported activities and initiatives. Additional NCI and
NINDS staff members may also be involved as needed (for example, by acting as
Collaborators or Coordinators).

Specific
responsibilities of NIH Program Staff will include the following:

1) Monitoring PBTC
progress: Actions necessary for monitoring may include, but are not
limited to, the following: regular communications with the PI and staff
members, periodic site visits for discussions with awardee research teams,
response audits to confirm activity reported from a PBTC clinical trial,
observation of field data collection and management techniques, fiscal review,
review of clinical trial reports submitted by the PBTC to NCI, review of the
PBTC’s annual progress report, and attendance at PBTC meetings. The
NCI retains, as an option, the right to conduct periodic external reviews of
progress.

2) Scientific
Liaison: Serving as a resource with respect to other ongoing NCI and
NINDS activities that may be relevant to the PBTC research efforts to identify
promising new leads, to facilitate compatibility with other NCI and NINDS
research projects, and to avoid unnecessary duplication of effort.

3) CTEP Assistance
in Clinical Trial Protocol Development: The clinical trial protocol must
be a detailed written plan of a clinical experiment mutually acceptable to the
PBTC and to the CTEP Protocol Review Committee (PRC). Communication at
the various stages of protocol development is encouraged as necessary to
promote protocol development and implementation. Protocols should be
preceded by a written Letter of Intent (LOI) from the PBTC declaring interest
in conducting a particular study. The PRC will formally review the LOI. Following
review, the NCI Project Scientist will provide a Program response to the PBTC
and will address the following issues: (a) the existence and nature of
concurrent clinical trials in the area of research, pointing out possible
duplication of effort; (b) information including relevant pharmacokinetic and
pharmacodynamic data concerning investigational agents; (c) availability of
investigational agents; (d) the PRC's assessment of the scientific rationale
and value of the proposed study, its design, and statistical requirements; (e)
appropriate inclusion of NCI Standard Protocol Language for CRADAs and CTAs in
the protocol; and (f) the implementation of the study, if indicated. The
LOI mechanism is designed for preliminary review and is recommended to expedite
clinical trial protocol development and implementation and to facilitate
agreement on study priority and design (for further discussion of these
mechanisms, see the DCTD Investigator's Handbook at http://ctep.cancer.gov/handbook/).

4) CTEP Review of
Proposed Clinical Trial Protocols: All PBTC protocols, including
protocols utilizing agents not sponsored by NCI, will be reviewed by the PRC,
which meets weekly and is chaired by the Associate Director, CTEP. Ad hoc
reviewers, external to NCI, will be utilized when deemed appropriate by the PRC
chairperson. Following the review of the clinical trial protocol by the
PRC, the NCI Project Scientist will provide the PBTC with a consensus review
that describes recommended modifications and other suggestions, as appropriate
(see the DCTD Investigator's Handbook, for further information regarding
protocol review at CTEP). The major considerations relevant to Protocol
Review by CTEP include:

a) the strength of
the scientific rationale supporting the study;

b) the clinical
importance of the question being posed;

c) the avoidance of
unnecessary duplication with other ongoing studies;

d) the
appropriateness of study design;

e) consistency with
development plans for particular IND agents;

f) a satisfactory
projected accrual rate and follow-up period;

g) patient safety;

h) compliance with
federal regulatory requirements;

i) adequacy of data
management;

j) appropriateness
of patient selection, evaluation, assessment of adverse events, response to
therapy and follow-up; and

k) methods of
monitoring and reporting to NCI to be used.

If a proposed clinical trial protocol is disapproved, the
specific reasons for lack of approval will be communicated in writing by the
NCI Project Scientist to the PBTC as a consensus review within 30 days of
protocol receipt by the NCI. NCI will not provide investigational agents
or permit expenditure of NCI funds for a clinical trial protocol that it has
not approved. The NCI Project Scientist will be available to assist the PBTC
in developing a mutually acceptable protocol, consistent with the research
interests, abilities and strategic plans of the PBTC and of the NCI.

5) CTEP Protocol
Amendment Review: Any change to the protocol document subsequent
to its approval by CTEP must be submitted in writing for review and approval
prior to implementation (see Section 8.6 – The Investigator’s
Handbook for further discussion of these procedures).

6) CTEP Involvement
in Auditing of Member Institutions: The Clinical Trials Monitoring Branch of
CTEP will coordinate with the PBTC the performance of on-site audits at PBTC
Member Institutions, which are to occur at approximately 2-3 year
intervals. The Clinical Trials Monitoring Branch will review audit
results and the corrective plans developed by the PBTC in response to the
audits.

7) CTEP Involvement
in Imaging Research: The NCI Imaging Research Coordinator will advise the
PBTC Steering Committee (through the NCI Project Scientist) with respect to
ongoing NCI activities and research opportunities related to the application of
imaging in drug development. He/she will participate in CTEP review of
PBTC protocols with imaging components and will assist the NCI Project
Scientist and the NINDS
Project Coordinator in
the overall review of PBTC imaging research activities and accomplishments.

8) CTEP Involvement
in Radiation Oncology Research: The NCI Radiation Oncology Research
Coordinator will advise the PBTC Steering Committee (though the NCI Project
Scientist) with respect to ongoing NCI activities and research opportunities
related to radiation therapy for pediatric brain cancers. He/she will
participate in CTEP review of PBTC protocols with radiation therapy components
and will assist the NCI Project Scientist in the overall review of PBTC
radiation oncology research activities and accomplishments.

9) CTEPInvolvement
in Clinical Trial Protocol Closure: Protocol closure is primarily the
responsibility of the PBTC and the specific Protocol Committee. The NCI
Project Scientist will also monitor clinical trial protocol progress and may
request protocol closure to further patient accrual for the following reasons:
(a) insufficient accrual rate; (b) accrual goal met; (c) poor protocol
performance; (d) patient safety or regulatory concerns; (e) study results are already
conclusive; and (f) emergence of new information that diminishes the scientific
importance of the study question. NCI will not provide investigational
agents or permit expenditures of NCI funds for a study after requesting closure
(except for patients already on-study).

10) Data Management
and Analysis Review: NCI Biometrics Research Staff will review
mechanisms established by the PBTC for data management and analysis. When
deemed appropriate, staff will make recommendations to ensure that data
collection and management procedures are adequate for quality control and
analysis and as simple as appropriate in order to encourage maximum
participation of physicians entering patients and to avoid unnecessary
expense. The NCI will have access to all data, although they remain the
property of the awardee institution. Data must also be available for
external monitoring as required by NCI's agreement with the FDA relative to the
NCI's responsibility as drug sponsor.

11) Data and Safety
Monitoring Plan: The NCI Program Official, assisted by the
Biostatistical Research Branch (BRB) staff, will assess PBTC compliance with
NCI and NIH established policies on Data and Safety Monitoring Plans. The
NCI Project Scientist must review and approve the PBTC’s Data and Safety
Monitoring Plan. One or more CTEP staff will serve as non-voting members
on the PBTC’s Data and Safety Monitoring Committee (DSMC), should the
Data and Safety Monitoring Plan (DSMP) specify a DSMC.

12) PBTC
Meetings: The NCI Program Official and Project Scientist as well as the NINDS Project
Coordinator will attend
semiannual PBTC meetings to discuss relevant scientific information, to discuss
progress in the clinical trials, and to discuss the status of newly available
investigational agents and other research opportunities in order to plan future
activities. Other NCI staff members (e.g., from the Investigational Drug
Branch, Radiation Research Program, and Diagnostic Imaging Program) and NINDS staff members will attend as needed.

13) CTEP Involvement
in Investigational New Drug (IND) Applications: The NCI Program Official
and Project Scientist, assisted by the Chief, Regulatory Affairs Branch (RAB),
CTEP, will advise investigators of specific requirements and changes in
requirements concerning IND sponsorship that the FDA may mandate. Investigators
performing trials under cooperative agreements will be expected, in cooperation
with the NCI, to comply with all FDA monitoring and reporting requirements for
investigational agents.

14) CTEP Review of
Federally Mandated Regulatory Requirements: The Chief, Clinical Trial
Monitoring Branch (CTMB), through the NCI Program Official and Project
Scientist, will advise the PBTC regarding mechanisms to meet FDA regulatory
requirements for studies involving DCTD-sponsored investigational agents
and OHRP requirements for the protection of human subjects by PBTC
institutions.

15) Access to
Data: The NCI will have access to all data generated under this
cooperative agreement and may periodically review the data. Data must
also be available for external monitoring as required by NCI's Drug Master File
Agreement with the FDA relative to the responsibility of the NCI as an IND agent sponsor. Data from studies of non-NCI-sponsored agents must be
available for external monitoring as described in the policies and procedures
established by the PBTC for on-site auditing of clinical trials
data. The awardee will retain custody and primary rights to the data
consistent with current HHS, PHS and NIH policies. The awardee will comply with
the data access provisions of applicable CTAs and CRADAs, and when these
agreements are in place the Industry Sponsor will have complete access to the
data for any and all regulatory filings.

16) Access to Agents
for Pre-Clinical Testing: For NCI-sponsored IND agents, NCI will
facilitate transfer of material to investigators with a Materials Transfer
Agreement (MTA).

17) CTEP Review of
Progress: Performance of the PBTC will be reviewed at least annually by
the NCI Project Scientist and Program Official on the basis of the information
provided at the semiannual and other meetings, in the annual progress reports
and in the CDUS reports submitted to CTEP for each of the PBTC’s clinical
trials. Insufficient patient accrual or progress, or noncompliance with
the terms of award, including these Terms and Conditions of Award, may result
in a reduction of budget, withholding of support, suspension, or termination of
the award.

18) Potential
Expansion of PBTC Scope: Contingent on the availability of funds, NCI staff
members in conjunction with NINDS will be responsible for developing an RFA for
competitive supplements to expand the scope of the PBTC award by innovative
clinical trials conducted in non-PBTC institutions.

The NCI Project Scientist
and the NINDS Project Coordinator as well as other NIH staff members acting as
Collaborators or Coordinators will not attend peer review meetings of renewal
(competing continuation) and/or supplemental applications. If such
participation is essential, the NCI Project Scientist will seek NCI waiver
according to the NCI procedures for management of conflict of interest if such
participation is deemed necessary. The NINDS Project Coordinator will
seek analogous waiver.

Additionally,
an NCI Program Director acting as Program Official will be responsible for the
normal scientific and programmatic stewardship of the award and will be named
in the award notice. The NCI Program Official and Project Scientist may be the same
person. In that case, the individual involved will not attend peer review
meetings of renewal (competing continuation) and/or supplemental applications
or will seek NCI waiver as stated above.

2.A.3.
Collaborative Responsibilities

The PBTC
will have a Steering Committee as a governing body. The Steering
Committee will include as voting members the PBTC lead PI, one representative
from each Member Institution (site PI or another designated investigator), the
PI(s) directing the Operations Center and Statistics and Data Center, and a
patient/family representative. Each voting member
will have one vote. The NCI Project Scientist will serve as an advisory
(non-voting) member to the Steering Committee. The NINDS Project Coordinator as well
as additional NIH representatives may participate as advisors and observers in
the Steering Committee meetings as needed and will also not have voting rights.

The
Steering Committee will be responsible for the approval of any changes to the
PBTC organizational structure and PBTC Standard Operating Procedures. The
Steering Committee will have primary responsibility to establish priorities,
and to develop and provide preliminary approval of protocols (prior to
submission to NCI and final NCI approval), and to review progress. The Steering
Committee will be responsible for reviewing on a regular basis the performance
of the Operations Center and Statistics and Data Center and the performance of the ancillary
scientific activities (imaging, pharmacology, and biologic studies). The Steering Committee will be
responsible for assuring that deficiencies identified during these reviews are
adequately addressed in a timely manner. The Steering Committee will be responsible for
reviewing Member Institutions for adequate performance, and will have the
authority to place on probation and to suspend Members and to add new Members
to replace any members suspended from the PBTC. The Steering Committee will also establish a process
for the selection of the laboratories to perform laboratory studies associated
with individual clinical trial protocols. The Steering Committee will
authorize the spending of funds from the Biology/Pharmacokinetics Fund and the Patient Studies Research Fund.

2. A.
4. Arbitration Process

Any
disagreement that may arise on scientific/programmatic matters (within the
scope of the award), excluding patient safety issues or regulatory compliance,
between award recipients and the NIH may be brought to arbitration. An Arbitration Panel composed of three members will be
convened to review the CTEP decision and recommend an appropriate course
of action to the Director, DCTD. It will have
three members: a designee of the Steering Committee; one NCI designee; and a
third designee with expertise in the relevant area who is chosen by the other
two. In the case of individual disagreement, the first member may be
chosen by the individual awardee. This special arbitration procedure in no way
affects the awardee's right to appeal an adverse action that is otherwise
appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and
DHHS regulations 45 CFR Part 16.

A
suggested format for PBTC-specific information relevant to the progress summary
section of the Form PHS 2590 will be provided. Performance of the PBTC in
developing new LOIs and protocols should be discussed, as should the
performance of Member Institutions in participating in PBTC studies and the
performance of reference laboratories. An update on clinical trials that
were approved, activated, closed and/or completed during the relevant budget
period should be discussed in the progress summary. Plans pertaining to
clinical trial activities for the next budget period should be addressed as
well.

Clinical trials reporting requirements will be in agreement
with FDA regulations and NCI procedures. Interim reports of each activated and
ongoing clinical trial should be prepared for each PBTC semiannual meeting and
shall include specific data on patient/participant accrual as well as detailed
reports of treatment-associated morbidity. Quarterly accrual reports must be
provided as appropriate to CTEP for all active trials through the NCI’s
Instructions and Guidelines for CDUS reporting are at http://cancer.gov/reporting/cdus.html.

A final
progress report, invention statement, and Financial Status Report are required
when an award is relinquished when a recipient changes institutions or when an
award is terminated.

Section VII. Agency Contacts

We encourage your inquiries
concerning this funding opportunity and welcome the opportunity to answer
questions from potential applicants. Inquiries may fall into three areas:
scientific/research, peer review, and financial or grants management issues:

Human Subjects Protection:Federal regulations (45CFR46) require that
applications and proposals involving human subjects must be evaluated with
reference to the risks to the subjects, the adequacy of protection against
these risks, the potential benefits of the research to the subjects and others,
and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety Monitoring Plan:Data and safety monitoring is required for all types
of clinical trials, including physiologic toxicity and dose-finding studies
(phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative
trials (Phase III). Monitoring should be commensurate with risk. The
establishment of data and safety monitoring boards (DSMBs) is required for
multi-site clinical trials involving interventions that entail potential risks
to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:Investigators submitting an NIH application seeking
$500,000 or more in direct costs in any single year are expected to include a
plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their
institutions, on issues related to institutional policies and local IRB rules,
as well as local, State and Federal laws and regulations, including the Privacy
Rule. Reviewers will consider the data sharing plan but will not factor the
plan into the determination of the scientific merit or the priority score.

Policy
for Genome-Wide Association Studies (GWAS):NIH is interested in advancing genome-wide association
studies (GWAS) to identify common genetic factors that influence health and
disease through a centralized GWAS data repository. For the purposes of this
policy, a genome-wide association study is defined as any study of genetic
variation across the entire human genome that is designed to identify genetic
associations with observable traits (such as blood pressure or weight), or the
presence or absence of a disease or condition. All applications, regardless of
the amount requested, proposing a genome-wide association study are expected to
provide a plan for submission of GWAS data to the NIH-designated GWAS data
repository, or provide an appropriate explanation why submission to the
repository is not possible. Data repository management (submission and access)
is governed by the Policy for Sharing of Data Obtained in NIH Supported or
Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088.
For additional information, see http://grants.nih.gov/grants/gwas/.

Access
to Research Data through the Freedom of Information Act:The Office of
Management and Budget (OMB) Circular A-110 has been revised to provide access
to research data through the Freedom of Information Act (FOIA) under some
circumstances. Data that are (1) first produced in a project that is supported
in whole or in part with Federal funds and (2) cited publicly and officially by
a Federal agency in support of an action that has the force and effect of law
(i.e., a regulation) may be accessed through FOIA. It is important for
applicants to understand the basic scope of this amendment. NIH has provided
guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
Applicants may wish to place data collected under this funding opportunity in a
public archive, which can provide protections for the data and manage the
distribution for an indefinite period of time. If so, the application should
include a description of the archiving plan in the study design and include
information about this in the budget justification section of the application.
In addition, applicants should think about how to structure informed consent
statements and other human subjects procedures given the potential for wider
use of data collected under this award.

Sharing of
Model Organisms:NIH is committed
to support efforts that encourage sharing of important research resources
including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm).
At the same time the NIH recognizes the rights of grantees and contractors to
elect and retain title to subject inventions developed with Federal funding
pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement http://grants.nih.gov/archive/archive/grants/policy/nihgps_2003/index.htm).
All investigators submitting an NIH application or contract proposal, beginning
with the October 1, 2004 receipt date, are expected to include in the
application/proposal a description of a specific plan for sharing and
distributing unique model organism research resources generated using NIH
funding or state why such sharing is restricted or not possible. This will
permit other researchers to benefit from the resources developed with public
funding. The inclusion of a model organism sharing plan is not subject to a
cost threshold in any year and is expected to be included in all applications
where the development of model organisms is anticipated.

Inclusion of
Women And Minorities in Clinical Research:It is the policy
of the NIH that women and members of minority groups and their sub-populations
must be included in all NIH-supported clinical research projects unless a clear
and compelling justification is provided indicating that inclusion is
inappropriate with respect to the health of the subjects or the purpose of the
research. This policy results from the NIH Revitalization Act of 1993 (Section
492B of Public Law 103-43). All investigators proposing clinical research
should read the "NIH Guidelines for Inclusion of Women and Minorities as
Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html);
a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
The amended policy incorporates: the use of an NIH definition of clinical
research; updated racial and ethnic categories in compliance with the new OMB
standards; clarification of language governing NIH-defined Phase III clinical
trials consistent with the new PHS Form 398; and updated roles and
responsibilities of NIH staff and the extramural community. The policy
continues to require for all NIH-defined Phase III clinical trials that: a) all
applications or proposals and/or protocols must provide a description of plans
to conduct analyses, as appropriate, to address differences by sex/gender
and/or racial/ethnic groups, including subgroups if applicable; and b)
investigators must report annual accrual and progress in conducting analyses,
as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of
Children as Participants in Clinical Research:The NIH
maintains a policy that children (i.e., individuals under the age of 21) must
be included in all clinical research, conducted or supported by the NIH, unless
there are scientific and ethical reasons not to include them.

Required
Education on the Protection of Human Subject Participants:NIH policy
requires education on the protection of human subject participants for all
investigators submitting NIH applications for research involving human subjects
and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human
Embryonic Stem Cells (hESC):Criteria for
federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.
Only research using hESC lines that are registered in the NIH Human Embryonic
Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov). It is the responsibility
of the applicant to provide in the project description and elsewhere in the
application as appropriate, the official NIH identifier(s) for the hESC line(s)
to be used in the proposed research. Applications that do not provide this
information will be returned without review.

NIH Public Access Policy Requirement:In accordance with the NIH Public Access Policy (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html)
investigators must submit or have submitted for them their final, peer-reviewed
manuscripts that arise from NIH funds and are accepted for publication as of
April 7, 2008 to PubMed Central (http://www.pubmedcentral.nih.gov/), to be made publicly
available no later than 12 months after publication. As of May 27, 2008,
investigators must include the PubMed Central reference number when citing an
article in NIH applications, proposals, and progress reports that fall under
the policy, and was authored or co-authored by the investigator or arose from
the investigator’s NIH award. For more information, see the Public
Access webpage at http://publicaccess.nih.gov/.

Standards
for Privacy of Individually Identifiable Health Information:The Department of Health and Human Services (DHHS)
issued final modification to the "Standards for Privacy of Individually
Identifiable Health Information", the "Privacy Rule", on August
14, 2002. The Privacy Rule is a federal regulation under the Health Insurance
Portability and Accountability Act (HIPAA) of 1996 that governs the protection
of individually identifiable health information, and is administered and enforced
by the DHHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of
the Privacy Rule reside with the researcher and his/her institution. The OCR
website (http://www.hhs.gov/ocr/)
provides information on the Privacy Rule, including a complete Regulation Text
and a set of decision tools on "Am I a covered entity?" Information
on the impact of the HIPAA Privacy Rule on NIH processes involving the review,
funding, and progress monitoring of grants, cooperative agreements, and
research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within
specified page limitations. For publications listed in the appendix and/or
Progress report, internet addresses (URLs) must be used for publicly accessible on-line journal articles. Unless otherwise specified in this solicitation, Internet addresses (URLs) should not be used to provide
any other information necessary for the review because reviewers are
under no obligation to view the Internet sites. Furthermore, we caution
reviewers that their anonymity may be compromised when they directly access an
Internet site.

Healthy People 2010:The Public Health Service (PHS) is committed to
achieving the health promotion and disease prevention objectives of
"Healthy People 2010," a PHS-led national activity for setting
priority areas. This FOA is related to one or more of the priority areas.
Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:This program is described in the
Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the
intergovernmental review requirements of Executive Order 12372 or Health
Systems Agency review. Awards are made under the authorization of Sections 301
and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and
under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are
subject to the terms and conditions, cost principles, and other considerations
described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to
provide a smoke-free workplace and discourage the use of all tobacco products.
In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits
smoking in certain facilities (or in some cases, any portion of a facility) in
which regular or routine education, library, day care, health care, or early
childhood development services are provided to children. This is consistent
with the PHS mission to protect and advance the physical and mental health of
the American people.

Loan Repayment Programs:NIH encourages applications for educational loan
repayment from qualified health professionals who have made a commitment to
pursue a research career involving clinical, pediatric, contraception,
infertility, and health disparities related areas. The LRP is an important
component of NIH's efforts to recruit and retain the next generation of
researchers by providing the means for developing a research career unfettered
by the burden of student loan debt. Note that an NIH grant is not required for
eligibility and concurrent career award and LRP applications are encouraged.
The periods of career award and LRP award may overlap providing the LRP
recipient with the required commitment of time and effort, as LRP awardees must
commit at least 50% of their time (at least 20 hours per week based on a 40
hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov.